Neuropeptides, when released into the pulmonary micro-environment, can enhance or inhibit airway contractile responses. Although there are many peptides that can be released in the lung, there is good reason to believe that the excitatory physiological effects of substance P (SP) and neurokinin (NKA) are counterbalanced by the inhibitory effects of vasoactive intestinal peptide (VIP). It is now well established that the physiological effects of SP, NKA, and VIP are limited by their degradation at or near the site of their release. Not only are SP, NKA, and VIP subject to enzymatic degradation, but there is good evidence to suggest that the expression or activity of the enzymes that cleave these peptides is also modulated. For example, in an inflammatory micro- environment, such as may be found in the asthmatic lung, the functional loss of the enzymes that limit SP and NKA effects could enhance the phlogistic responses elicited by SP and NKA. In the non-inflamed lung we would expect the inhibitory actions of VIP would counteract the contractile effects of SP and NKA. However, when the enzymes with the capacity to degrade SP and NKA are inhibited, the contractile and microvascular effects of SP and NKA may be so great as to prevent a counterbalancing action of VIP. This loss of the potential homeostatic effects of VIP may be especially devastating since VIP degradation may occur through the action of enzyme systems that are not inhibited, or may even be enhanced, in an inflammatory microenvironment. As a result, airway inflammation has the potential to differentially enhance the pro- phlogistic effects of SP/NKA and diminish the homeostatic effects of VIP. Based on this information, we propose the following hypothesis: Release and cleavage of SP, NKA and VIP is modified by an inflammatory pulmonary micro-environment. To test this hypothesis we propose to examine the cleavage and inactivation of exogenously administered and endogenously released SP/NKA/VIP in isolated guinea pig lungs and in intact guinea pigs. Comparisons will be made between lungs with experimentally induced chronic inflammation and normal lungs.